tbuckley/cabot-search huggingface dataset:
PB2077: POD12 AND POD24 – A NEW SURROGATE MARKER IN MANTLE CELL LYMPHOMA TREATMENT?
Authors: J. Freitas, D. Pereira, C. Moreira, S. Chacim, N. Domingues, A. Espírito Santo, Â. Martins, I. Oliveira, L. Viterbo, I. Moreira, J. Mariz
Journal: HemaSphere (2022)

Background: Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin’s lymphoma (NHL) with a generally aggressive, albeit heterogeneous, clinical course. It can present either with asymptomatic monoclonal lymphocytosis or non-bulky nodal/extra nodal disease with minimal symptoms or with a progressive generalized lymphadenopathy, cytopenia, splenomegaly and extra-nodal disease. Despite the paradigm shift in the treatment landscape, there is still a subset of patients with a worse prognosis. Novel surrogate markers had been emerging in other entities such as POD24 (progression of disease within 2 years) in follicular lymphoma, which is not still studied in MCL. Aims: Evaluate the prognostic factor of POD within 12months (POD12) and 24months (POD24) after first line treatment in MCL patients Methods: We retrospectively evaluated 118 patients (pts) with MCL between Jan/2010 and Dec/2020. Survival analysis was evaluated using Kaplan-Meier curves and the identification of predictive factors by the Cox regression method. Results: 83 (70.3%) pts were male and the median age at diagnosis was 67 years [39-89]. 114 (96.6%) pts had stage III/IV at diagnosis, 85.6% ECOG <2, 81.4% bone marrow involvement, 79.5% diffuse lymphadenopathies, 45.8% B symptoms, 33.9% splenomegaly, 30.5% leukemic phase, 25.4% extra-nodal disease, 25.4% gastrointestinal involvement and 23.7% bulky disease (>5cm). The median LDH at diagnosis was 212U/L. According to the MIPI score, 82pts (69.5%) were low risk, 13 (11.9%) intermediate and 22 (18.6%) high risk. The median lines of therapy was 2 [1-5] and 32pts (27.1%) underwent autologous stem cell transplant after first line therapy. Overall survival (OS) at 2 and 5 years was 81% and 56.6%. POD12 and POD24 occurred in 39 dts (33.1%) and 56 (47.5%), respectively. Patients with POD12 had a 2‐year OS of 44.5% and 5‐year OS of 18.4% compared to 98.7% and 75% for patients without early POD12, respectively. Regarding POD24, 5‐year OS of 20.9% compared to 84.4%, respectively, for patients without early POD24.The Kaplan‐Meier curve showed an inferior OS for patients with early POD compared to those not relapsing within 12 months and/or 24 months (P < 0.001) [figure ​1 and 2]. Univariable analysis showed that ECOG ≥2, leukemic phase, elevated LDH, MIPI score, POD12 and POD24 were associated with inferior OS. In multivariable analysis, clinical factors predictive of inferior OS were POD12, POD24, high risk MIPI, elevated LDH and ECOG ≥2. Image:Summary/Conclusion: POD12 and POD24 are associated with unfavorable outcomes and worse OS. These results support the potential to use these criteria as primary surrogate endpoints. Survival analysis did not allow us to conclude which of the endpoints have the greatest discriminative power in OS, so prospective studies with larger sampling will be necessary.
P1686: VARIATION IN DIAGNOSTIC REQUESTS AND OUTCOMES FOR HEREDITARY THROMBOPHILIA -OVER TESTING AND UNDER TESTING
Authors: S. isaacs, W. Cerfontein, S. Isaacs, N. Mashigo, C. Swanepoel
Journal: HemaSphere (2022)

Background: Heritable thrombophilia is a multiple gene disorder with high mortality and morbidity. Genetic risk factors associated with Venous Thromboembolism have been linked to mutations in the genes of the coagulation/anticoagulation system. The more prevalent inherited risk factors are the gain-of-function mutations in coagulation factors V and II, namely factor V-Leiden (FVL and/or F5G1691A (FVR506Q,)) and prothrombin/Factor II (FII) F2G20210A. The epidemiology of the FVL and FII mutations has not been well studied within either the South African or African context. Aims: To conduct a retrospective audit to determine the total number of FVL and FII tests requested by clinicians and the prevalence of FII mutations at Tygerberg hospital, and screen a novel gain of function mutation, Prothrombin Yukuhashi, in exon 14 of the FII gene. Methods: Test requests were analysed over a period of 11 years (2007-2017). 50 patients were randomly selected whose peripheral blood samples were received by the National Health Laboratory Services (NHLS) Molecular haematology diagnostic laboratory from clinicians requesting the FVL and FII assay. Exon 14 was amplified using reference primers and verified by PCR followed by bidirectional sequencing to identify the presence of the mutation. Statistical anlysis of all data was performed with the help of a statistician. Results: For the audit, 80.4% of the requests were for FVL, 3.8% were for FII and 15.8% of the requests were for FVL and FII together. The most tests were requested during 2013 when the implementation of a multiplex assay occurred. The mutational frequency for FVL was shown to be 3.3%, compared to FII which was 6.9%. Summary/Conclusion: The frequency of the FII mutation was more than double that of the FVL mutation, despite more than 80% of requests being for FVL alone. The study also showed that the Prothrombin Yukuhashi mutation was not prevalent in our cohort.
Abstract 694: E-slice: A novel 3D culture platform for precision medicine
Authors: Archana Gopalan, Thomas D. Gallup, Stephanie Wood, Jose Maldonado, Corina Margain, Nestor F. Esnaola, Min P. Kim, E. Scott Kopetz, Kyuson Yun
Journal: Cancer Research (2022)

Abstract The need for personalized medicine in oncology is widely accepted but translating this important concept into clinical practice has been challenging. Currently, the dominant platform for precision medicine utilizes genomics/sequencing-based assays to measure the expression and/or mutational profiles and then infer patient responses to therapies based on previous knowledge; however, this approach benefits less than 10-15% of patients with profiled tumors. Recognizing the inherent limitations of these inference-based methods, functional assays (e.g., organoids and PDX models) have been developed; however, these approaches also have significant limitations including high cost and time required to establish the models, low “take rates”, and destruction of the native tumor microenvironment (TME). To overcome these challenges, EMPIRI uses a novel 3D ex vivo tumor slice culture method (E-slices) that enables rapid, personalized drug sensitivity testing in intact patient tumor tissues. Major differentiators of the E-slice platform from other ex vivo methods include the use of chemically defined, serum-free medium, longitudinal viability measurements from the same tissue, tracking of dynamic responses to treatment over 2-3 weeks, and retention of the native TME and tissue architecture, unlike other approaches. In addition, E-slices can be generated from any solid tumor tested thus far (breast, lung, colorectal, pancreas, brain, head 7 neck, and others) from patient tumors directly and PDX and genetically engineered mouse models. In addition, because E-slices retain tumor-infiltrating immune cells in their native microenvironment and spatial topography of all cell types in the endogenous configuration, it sustains immune cell survival and proliferation and measures immunotherapy responses ex vivo. The E-slice method is compatible with biopsies as well as surgical samples. Importantly, it has been shown to accurately predict individual patient treatment responses to chemotherapies and targeted therapies in 4-12 days, paving the way for evidence-based personalized treatment selections in a clinically actionable time frame. In summary, we present a novel ex vivo 3D human tumor tissue drug sensitivity platform that faithfully replicates the patient tumor tissues and provides personalized treatment responses in a clinically actionable time frame. Citation Format: Archana Gopalan, Thomas D. Gallup, Stephanie Wood, Jose Maldonado, Corina Margain, Nestor F. Esnaola, Min P. Kim, E. Scott Kopetz, Kyuson Yun. E-slice: A novel 3D culture platform for precision medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 694.
P1125: CELESTIMO: A PHASE III TRIAL EVALUATING THE EFFICACY AND SAFETY OF MOSUNETUZUMAB PLUS LENALIDOMIDE VERSUS RITUXIMAB PLUS LENALIDOMIDE IN PATIENTS WITH RELAPSED OR REFRACTORY FOLLICULAR LYMPHOMA
Authors: L. Nastoupil, F. Morschhauser, C. W. Scholz, M. Bishton, S.-S. Yoon, P. Giri, M. C. Wei, A. Knapp, C.-C. Li, A. Bottos, H. Li, E. Purev, N. L. Bartlett
Journal: HemaSphere (2022)

Background: Despite significant progress with first-line immunochemotherapy, most patients with follicular lymphoma (FL) will eventually relapse with increasing refractoriness and decreasing duration of response to subsequent therapy lines (Rivas-Delgado et al. 2019). Mosunetuzumab (M) is a CD20xCD3 bispecific antibody that engages and redirects T-cells to eliminate malignant B cells (Sun et al. 2015). In an ongoing, pivotal Phase I/II trial of M monotherapy, patients with relapsed/refractory (R/R) FL who have received ≥2 prior treatment lines achieve deep and durable responses (NCT02500407; Budde et al. ASH 2021). Preliminary data from a Phase Ib study have suggested favorable safety and promising activity of M in combination with lenalidomide (Len), a potent immunomodulatory agent that has shown additive/synergistic activity with an anti-CD20 antibody in R/R indolent lymphoma (Leonard et al. 2019), in patients with R/R FL who have received ≥1 prior therapy (NCT4246086; Morschhauser et al. ASH 2021). The chemotherapy-free M-Len combination may represent a promising outpatient therapy option for future management of patients with R/R FL. The randomized, multicenter Phase III study has been initiated. Aims: CELESTIMO (NCT04712097) is a randomized, multicenter, open-label Phase III study evaluating the efficacy and safety of M-Len versus rituximab plus Len (R-Len) in patients with previously treated R/R FL. Methods: Patients must have histologically documented CD20+ FL (Grades 1–3a) requiring systemic therapy and have received ≥1 prior line of systemic therapy. Patients are randomized (1:1) to receive M-Len (M intravenously [IV] on Days [D] 1, 8 and 15 of Cycle [C] 1 [21-day cycle] and D1 of C2–12 [28-day cycles], plus Len orally [PO] on D1–21 of C2–12) or R-Len (R IV on D1, 8, 15 and 22 of C1 then on D1 of C3, 5, 7, 9, and 11, plus Len PO on D1–21 of C1–12 [all 28-day cycles]), and stratified by disease progression within 24 months of initial treatment (yes/no), number of prior lines of therapy (1 versus ≥2), and refractoriness to anti-CD20 therapy (refractory/non-refractory). All patients must provide informed consent. Results: The primary endpoint is progression-free survival (PFS) assessed by independent review committee; secondary endpoints include investigator-assessed PFS, complete and objective response, overall survival, and safety. Biomarkers predictive of response to M-Len and R-Len will also be investigated as exploratory endpoints. Summary/Conclusion: The study started recruitment in 2021 and plans to enroll ~400 patients from approximately 16 countries and 150 sites globally. Further study details will be presented.
PB2317: COINHERITANCE OF COMBINED FACTOR VII AND FACTOR XIII DEFICIENCY IS ASSOCIATED WITH A MILD BLEEDING PHENOTYPE IN PATIENT WITH NON-TRANSFUSION DEPENDENT THALASSEMIA
Authors: O. Alshareef, B. Allahyani, E. Alnasser
Journal: HemaSphere (2022)

Background: The coinheritance of FVII and FXIII is extremely rare. FVII and FXIII deficiency was common in the Saudi population. However, double heterozygous have not been described in hypercoagulable states such as thalassemia. This is a case of combined FVII and FXIII deficiency in a non-transfusion-dependent thalassemic presented with hemarthrosis. Aims: This report aims to describe a case of combined coagulation factor VII and factor XIII deficiency in non-transfusion dependent thalassemia. Methods: We conducted a retrospective chart review. Results: An 8-year-old boy known to have non-transfusion dependent thalassemia presented with painful knee swelling after significant trauma. He was pale, jaundiced, with absent palpable hepato-splenomegaly. Soft tissue ultrasound suggested hemarthrosis. Coagulation factors assays showed normal results with a notably combined deficiency of coagulation factors VII (<50% activity) and FXIII (<10% activity). During infancy, he had a history of prolonged oozing after circumcision. Since then, the child has had a history of multiple bleeding episodes post minor trauma that was controlled by fresh frozen plasma (FFP) transfusion. Moreover, with a significant history of traumatic subgaleal hematoma, he was admitted and received FFP and packed red blood cells (PRBCs). Summary/Conclusion: We have identified a previously unreported mild phenotypic combined FVII and FXIII deficiency in patients with hemoglobinopathy disorder. Hypercoagulable state in hemoglobinopathies might mitigate the bleeding phenotype of factor deficiency, though bleeding history should be thoroughly investigated in such cases.
P1531: HETEROGENEITY OF DISEASE-CAUSING GENOTYPES BETWEEN FAMILIES WITH HEREDITARY SPHEROCYTOSIS: A SINGLE-CENTER COHORT STUDY
Authors: R. Jimenez Heredia, L. Kager, P. Zeitlhofer, W. Novak, S. Eder, A. Segarra Roca, K. Nebral, M. Haimel, R. Geyeregger, O. Haas, K. Boztug
Journal: HemaSphere (2022)

Background: Hereditary spherocytosis (HS) is a phenotypically and genetically heterogeneous disease, in which erythrocytes are unable to maintain their normal biconcave shape due to genetic mutations in membrane/cytoskeletal proteins that play a role in structural morphologic stability. Recent progress in genomic analyses technologies has helped to shed light on the complexity of genotype/phenotype correlations within this orphan hemolytic red blood cell disorder. Aims: In this retrospective investigation, we aim to investigate the genotype-phenotype correlation based on the clinical severity of the disease and the gene-wise predicted pathogenicity comparison. Furthermore, we want to highlight the importance of next generation sequencing (NGS) technologies in the diagnosis of HS. Methods: We provide the results of a single-center study in Austria on a total of 69 patients (core group, N=35; affected family members, N=34) with HS, focusing on NGS results (both exome and panel sequencing), ancestry, laboratory findings, clinics, as well as genotype-phenotype correlations. Results: A pathogenic (N=59/69; core group, N=29/35) or likely pathogenic variant (N=6/69; core group N=3/35) was identified in 94% (core group 91%) of the patients, including 18 novel variants. Variants in ANK1 (46%; European ancestry 37%, non-European 9%) were most encountered, followed by SPTB (31%, all European) and SLC4A1 (14%; European 11%, non-European 3%). In three patients (9%, all European) we were unable to identify the genetic cause unequivocally. Except for a heterozygous intronic ANK1 c.1504-9G>A variant, which was identified in two unrelated European families, there was no overlap on causative variants. The majority of mutations (N=25; 81%) were of high impact and include frameshifts, N=14 (45%); nonsense, N=8 (26%); CNVs, N=2 (6%) and splice-site variants, N=1 (3%). Sufficient data for phenotype-genotype correlation testing were available for 56 patients (core group, N=35), and phenotypes were milder in the patients with SLC4A1 variants. Patients with ANK1 and SPTB variants had comparable phenotypes. Summary/Conclusion: To our knowledge, this is the first study describing genomics (N=69) and genotype-phenotype correlation (N=56) in patients with HS in Central-Europe. We were able to identify causative variants in 94% of the 69 patients, including atypical disease-causing genetic findings such as intronic and CNV mutations. This evidenced the compelling need of a combination of standardized NGS analysis and clinical deep investigation in order to accurately characterize and treat HS patients.
PB2227: HEALTH-RELATED QUALITY OF LIFE OVER TIME IN PEDIATRIC PATIENTS WITH SICKLE CELL DISEASE ADMITTED FOR VASO-OCCLUSIVE CRISIS.
Authors: C. Vuong, I. Moussa, L. Haverman, E. Rettenbacher, H. Heijboer, J. Twisk, K. Fijnvandraat, C. L. de Groot-Eckhardt
Journal: HemaSphere (2022)

Background: Sickle cell disease (SCD) is the most common inherited hemoglobinopathy characterized by chronic hemolytic anemia, vaso-occlusive crises (VOCs), multi-organ damage and an impaired health-related quality of life (HRQoL). Previous studies have shown that the occurrence of VOCs affects the HRQoL substantially in children with SCD. However, there is limited evidence about the HRQoL changes over time following hospitalization for VOC. Aims: The aim of this study is to evaluate the longitudinal impact of hospital admission for VOCs on the HRQOL in pediatric patients with SCD. Methods: In this retrospective cohort study, children between the age of 8 and 18 years with SCD treated at the Amsterdam University Medical Centers were included. As part of standard care, these children complete once a year Patient Reported Outcomes measures (PROMs) on the KLIK PROM portal (www.hetklikt.nu). HRQoL was measured with the Pediatric Quality of Life Inventory (PedsQL) (score ranging from 0-100, a higher score indicates better QoL). Data were collected from the medical files of patients, who filled out at least two PedsQL questionnaires between 2012 and 2021. The effect of the occurrence and frequency of hospital admissions for VOCs on the HRQoL was evaluated using a linear mixed model 3, 6, 9 and 12 months after hospital admission, adjusted for age and SCD genotype. Results: In total, 109 children were included with a median age of 11.8 years (IQR: 9.2 – 14.2), including 72 patients (66%) with the severe genotype: HbSS or HbSβ0. During follow-up, 45 patients (41%) were admitted to the hospital for a VOC. If hospitalization occurred 6 and 12 months prior to the PedsQoL measurement, a decrease of 3.61 (p=0.049) and 3.80 points (p=0.007) in HRQoL respectively, was seen compared to patients without hospitalization. As for the frequency of VOC admission in the preceding 12 months, a decrease of 2.28 points in HRQoL was observed for every additional admission (p=0.012). Summary/Conclusion: The negative longitudinal association between hospital admission for VOC and HRQoL in pediatric patients with SCD gets worse and persists up to 12 months. These findings highlight the importance of monitoring using PROMS in clinical practice and extra attention and support for the negative consequences of the hospital admission for VOCs, affecting the HRQoL.
P1623: ROLE OF HLA GENES IN DEVELOPMENT OF HLA-ALLOIMMUNIZATION IN BLOOD RECIPIENTS
Authors: E. Butina, F. Sherstnev, A. Yovdiy, O. Maksimov
Journal: HemaSphere (2022)

Background: The main adverse effects of HLA-alloimmunization are transfusion failure and the need for additional platelet transfusions, febrile reactions, and the threat of fatal bleeding. The individual prediction of the risk of alloimmunization remains an unresolved problem. It seems relevant to study the relationship between the HLA genotype and the probability of alloimmunization of recipients as a result of blood transfusions. Aims: Assess the genetic predisposition of recipients to the development of HLA alloimmunization. Methods: Immunohematological and genetic studies were performed in 61 patients (22 men and 39 women) who received from 6 to 32 transfusions of blood components (median 11) during the previous treatment in a hematology clinic in 2019-2021. All blood components were leukoreduced. Patient age ranged from 3 to 78 years (median 48 years). Acute leukemia was diagnosed in 34 patients, myelodysplastic syndrome - in 10, aplastic anemia - in 8, other blood diseases - in 9. Typing of HLA DRB1, DQA1, DQB1 gene was performed by real-time polymerase chain reaction using equipment and reagents from DNA- technology (Russia). Statistical analysis was performed using the chi-square test. Results: Based on the results of the study of antilymphocyte antibodies, patients were divided into two groups: HLA-nonimmunized (n=31) and HLA-immunized (n=30). The Panel Reactive Antibody in 3 out of 30 alloimmunized patients was 25-49%, in 12 - 50-74%, in 15 patients - 75-100%. When analyzing the results of immunogenetic examination, statistical differences were established in the frequency of detection of HLA-alleles and haplotypes in the genotypes of HLA-alloimmunized and nonimmunized recipients (Table). Table. - Frequency of detection of HLA-DRB1-DQA1-DQB1 haplotypes in HLA-alloimmunized and HLA-non-alloimmunized patients HLA-DRB1-DQA1-DQB1 haplotypes Frequency of detection of HLA haplotypes p HLA-nonalloimmunized patients, n=31 HLA- alloimmunized patients, n=30 абс. % абс. DRB1*15-DQA1*01:02-DQB1*06:02-8 14 45.2 7 23.3 0.12 DRB1*01-DQA1*01:01-DQB1*05:01 12 38.7 9 30 0.65 DRB1*03-DQA1*05:01-DQB1*02:01 2 6.5 8 26.7 0.07 DRB1*04-DQA1*03:01-DQB1*03:02 1 3.2 9 30 0.01 DRB1*07-DQA1*02:01-DQB1*02:01 4 12.9 6 20 0.69 DRB1*13-DQA1*01:03-DQB1*06:02-8 3 9.7 7 23.3 0.27 DRB1*16-DQA1*01:02-DQB1*05:02 6 19.4 0 0 0.03 DRB1*11-DQA1*05:01-DQB1*03:01 3 9.7 4 13.3 0.96 Summary/Conclusion: A genetically determined predisposition to the development of HLA-alloimmunization as a result of blood transfusions is associated with the presence of HLA-alleles DRB1*04, DQA1*03:01, DQA1*05:01 and HLA-haplotype DRB1*04-DQA1*03:01-DQB1*03:02 in the genotypes of recipients. The probability of antibody production is reduced in patients with HLA-alleles DRB1*16, DQA1*01:02, DQB1*05:02 and HLA-haplotype DRB1*16-DQA1*01:02-DQB1*05:02.